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A more recent version of this article appeared on June 1, 2002
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Submitted on September 7, 2001
Revised on March 5, 2002
Accepted on March 18, 2002
1 Department of Biochemistry, University of Washington, Seattle, WA 98195
2 Monoclonal Antibody Core Facility, Hope Heart Institute, Seattle, WA 98104
3 Departments of Biochemistry and Medicine, University of Washington, Seattle, WA 98195
* Corresponding author. E-mail address: bornsten{at}u.washington.edu.
The matricellular protein, thrombospondin 2 (TSP2), regulates a variety of cell-matrix interactions. A prominent feature of TSP2-null mice is increased microvascular density, particularly in connective tissues synthesized after injury. We investigated the cellular basis for the regulation of angiogenesis by TSP2 in cultures of murine and human fibroblasts and endothelial cells. Fibroblasts isolated from murine and human dermis synthesize TSP2 mRNA and secrete significant amounts of immunoreactive TSP2, whereas endothelial cells from mouse lung and human dermis did not synthesize TSP2 mRNA or protein. Recombinant mouse TSP2 inhibited growth of human microvascular endothelial cells (HMVEC) mediated by bFGF, IGF-1, EGF, and VEGF. HMVEC exposed to TSP2 in the presence of these growth factors had a decreased proportion of cells in S and G2/M phases. HMVEC cultured with a combination of bFGF, IGF-1, and EGF displayed an increased proportion of nonviable cells in the presence of TSP2, but the addition of VEGF blocked this TSP2-mediated impairment of cell viability. TSP2-mediated inhibition of DNA synthesis by HMVEC in the presence of VEGF was not affected by the broad spectrum caspase inhibitor, zVAD-fmk. Similar findings were obtained with TSP1. Taken together, these observations indicate that either TSP2 or TSP1 can inhibit HMVEC proliferation by inhibition of cell-cycle progression and induction of cell death, but the mechanisms responsible for TSP2-mediated inhibition of cell-cycle progression are independent from those leading to cell death.
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